Project Summary RBC alloimmunization represents a major complication of chronic transfusion therapy. For those patients who are unfortunate enough to generate multiple alloantibodies, provision of compatible antigen negative RBCs can be both time and resource intensive. In rare cases, this can result in an inability to locate an otherwise life-saving therapy. Among chronically transfused patients, those with Sickle Cell Disease (SCD) suffer disproportionately from alloimmunization. This proposal sets out to determine the cellular and molecular controllers of responder vs. non-responder status in SCD patients. Our overarching hypothesis is that differential control of T follicular helper cell (TFH) subset differentiation by cytokines is responsible for alloimmunization responses in general, and for responder vs. non-responder status in SCD patients in particular. This proposal combines studies of experimentally tractable mouse models of specific cytokine deficiency with cytokine driven TFH differentiation assay performed on human lymphocytes from both healthy donors and SCD patients. By providing a molecular mechanism capable of explaining and predicting responder status among SCD patients, this proposal could have a significant impact on the transfusion care of SCD patients. Knowing a patient's responder status prior to initiating transfusion therapy would allow for a more personalized and tailored therapeutic approach. For example, we could determine which patients are likely to get the most benefit from extended phenotype matching protocols. Ultimately, understanding the molecular regulators that dictate responder status would also help in the identification of potential targets for future therapeutic intervention.